Novel pathogenic variants in an Indian cohort with epidermolysis bullosa: Expanding the genotypic spectrum

BackgroundEpidermolysis bullosa (EB) is a genodermatosis characterized by skin fragility and blisters with variable severity. Patients with Dystrophic EB (DEB) or Junctional EB (JEB) mainly present to clinic due to greater functional impairment. Pathogenic sequence variations in COL7A1 are implicated in DEB.ObjectiveWe have tried to decipher the molecular spectrum and genotype phenotype correlation of 21 Indian patients with EB.MethodsNext generation sequencing (NGS) was performed to determine the pathogenic variants. Sanger sequencing was also done for validation of the variants in eleven individuals.ResultsPathogenic variants were detected in 20 individuals (diagnostic yield of 95%). Majority of them (90%) had sequence variation in COL7A1 while two had pathogenic variants in ITGB4 and KRT14 respectively. Out of the 18 patients confirmed to have DEB, 3 had Dominant DEB (DDEB) whereas 15 patients had Recessive DEB (RDEB). Amongst 23 sequence variations identified, 12 were found to be novel (3 were missense, 5 were premature termination codon variants while 4 were splice-site changes).ConclusionGenotype phenotype correlation was noted with milder manifestations in those with dominant inheritance types. Exact molecular diagnosis can be ascertained by NGS in majority of cases.     

后路半椎体切除矫治半椎体所致脊柱侧后凸畸形

[目的]评价后路半椎体切除术治疗半椎体所致脊柱侧后凸畸形的临床效果。[方法]2000年5月~2005年11月,采用后路半椎体切除及矫形固定融合术治疗14例完全分节半椎体所致脊柱侧后凸畸形患者。年龄2.5~14.4岁,平均7.4岁,半椎体均为侧后方半椎体,其中胸椎7例,腰椎7例。[结果]手术时间2~7 h,平均4.7h,术中出血量150~2 500 m l,平均560 m。l固定节段2~8个椎体,平均3.5。术后随访6~36个月。平均15.6个月。术后站立位脊柱正侧位X线片示冠状面Cobb's角由术前46.2°矫正到17.3°,平均矫正率62.6%,矢状面Cobb's角由术前48.3°矫正至术后16.2°,平均矫正率68.7%。终末随访时冠状面Cobb's角平均21.7°,丢失4.4°,矢状面Cobb's角平均18.7°,丢失2.5°。围手术期并发症包括:伤口愈合不良2例,术中术后椎弓根螺钉切割椎体2例。[结论]后路半椎体切除可直接去除致畸因素,在冠状面及矢状面均获得良好的矫形效果,与前后路手术相比可缩短手术时间,减少创伤,适用于从胸段到腰段的半椎体畸形。     

The molecular basis for inherited bullous diseases

In the past 5 years enormous progress have been made in our understanding of the molecular basis for a number of inherited skin diseases characterized by easy blistering of the skin and the mucous membranes after minor physical trauma. This increased fragility of the skin or its appendages is due to molecular defects in genes coding for different intra- and extracellular structural proteins which are responsible for mechanical strength at their sites of expression. These diseases encompass the group of epidermolysis bullosa and disorders of cornification such as bullous forms of ichthyosis, palmoplantar keratoderma, and pachyonychia congenita. On the basis of clinical, morphological, and ultrastructural observations the epidermolysis bullosa group has been divided into three major categories. In epidermolysis bullosa simplex blister formation appears within the basal cell layer of the epidermis, and many mutations have been found in the genes of keratin 5 and 14 which are both expressed in basal keratinocytes. Epidermolytic hyperkeratosis leads to an epidermal separation in the suprabasal cell layers. In these patients numerous point mutations have now been described in the suprabasally expressed genes of keratin 1 and 10. In ichthyosis bullosa of Siemens blisters occur in the more upper suprabasal epidermis coincidental with the expression of keratin 2e, and mutations have been detected in the corresponding gene. In epidermolytic palmoplantar hyperkeratosis the suprabasal epidermal splitting is restricted to palms and soles of the patient. In keratin 9, which reveals such an exclusive expression pattern, molecular defects have indeed been recognized. Most recently in two different clinical subtypes of pachyonychia congenita, which is characterized by defective nails and focal palmoplantar hyperkeratosis, point mutations have been found in the genes coding for keratins 6, 16, and 17. In junctional epidermolysis bullosa the separation takes place within the dermal-epidermal basement membrane at the level of the lamina lucida, and mutations have been found in three genes coding for different laminin chains, in the ₄ gene of ₆₄ integrin, and in the gene of collagen XVII. In dystrophic epidermolysis bullosa the tissue separation occurs beneath the basement membrane within the papillary dermis at the level of the anchoring fibrils, and several mutations have been identified in the collagen VII gene. The rapid unraveling of molecular defects in these disabling or even lethal inherited skin diseases makes possible a more precise and earlier prenatal diagnosis, creates new options for suitable therapeutic regimens, and even offers the hope of curing these diseases by means of somatic cell gene therapy.Abbreviations BM Basement membrane - BPAg Bullous pemphigoid antigen - DEB Dystrophic epidermolysis bullosa - EB Epidermolysis bullosa - EBS Epidermolysis bullosa simplex - EHK Epidermolytic hyperkeratosis - EPPK Epidermolytic palmoplantar keratoderma - IBS Ichthyosis bullosa of Siemens - JEB Junctional epidermolysis bullosa - KIF Keratin intermediate filaments - NC Noncollagenous domain - NEPPK Nonepidermolytic palmoplantar keratoderma - PC Pachyonychia congenita     

后路凸侧椎板楔形截骨经肋椎关节松解胸椎间隙治疗青少年重度脊柱侧后凸

【摘要】 目的：评价经后路凸侧椎板楔形截骨经肋椎关节松解胸椎间隙矫形治疗青少年重度脊柱侧后凸畸形的安全性和早期临床效果。方法：2014年5月~2016年12月对我院15例青少年重度脊柱侧后凸患者行经后路凸侧椎板楔形截骨经肋椎关节松解胸椎间隙手术治疗,术前仅1例严重脊柱侧后凸患者行头盆环牵引。男6例,女9例,年龄13～18岁（16.1±1.6岁）。其中先天性脊柱侧后凸3例,特发性11例,神经纤维瘤病性1例。术前侧凸Cobb角82°～144°（102.5°±17.6°）,侧凸的柔韧性为6.4％～28.5％[（21.56±5.70）%];后凸50°～95°（68.1°±15.3°）,冠状位躯干偏移距离（C7中垂线与骶骨中垂线距离）2.0～6.8cm（3.40±1.37cm）。术前四肢肌力及感觉均正常。观察治疗效果。结果：椎板楔形截骨5.20±0.56个（4~6个）,松解椎间隙5.20±0.56个（4~6个）,手术时间6.1～7.9h（7.00±0.51h）,术中出血量1050～2500ml（1450.0±521.3ml）。术后侧凸Cobb角18°～40°（28.0°±6.6°）,矫正率72.5%;后凸22°～42°（27.8°±6.1°）,矫正率58.4%;冠状位躯干偏移距离0～2cm（0.85±0.74cm）,矫正率72.8%。随访25～41个月（33.1±5.4个月）。末次随访时侧凸Cobb角19°～43°（30.0°±6.9°）,矫正率70.6%;后凸22°～42°（28.6°±6.5°）,矫正率57.2%;冠状位躯干偏移距离0.2～2.3cm（1.10±0.72cm）,矫正率71.3%。无胸膜破裂,无假关节形成,无内固定断裂及松动,矫正度无显著丢失。1例患者术前骨盆牵引发生钉道感染,经局部换药及抗生素应用,2周后感染控制;1例术后第3天发生十二指肠系膜上动脉综合征,采取禁食水、持续胃肠减压、维持水电解质平衡、左侧卧位,术后2周痊愈;1例T4左侧椎弓根螺钉侵入椎管压迫神经,术后5h发生左下肢不完全性瘫痪,术后8h去除T4左侧椎弓根螺钉,术后5个月左下肢功能完全恢复。结论：采用后路凸侧椎板楔形截骨经肋椎关节松解胸椎间隙治疗青少年重度脊柱侧后凸畸形,不需要剥离椎体侧方胸膜,手术解剖层次表浅和创伤小,不仅有助于增加脊柱柔韧性,而且可提供足够的压缩和闭合空间来矫正脊柱侧后凸,能获得良好的脊柱三维矫正。     

Round Pendant Around the Neck–Thyroid. A Review

The rare situation of thyroid stone is discussed with literature review and case report. A case of isolated solitary stone of the thyroid is documented here. There are incidences of calcification in the thyroid gland commonly associated with carcinoma thyroid and multinodular goiter. But solitary stone of thyroid is reported rarely and one such case is reported from India. The possibility of malignancy is high, in case of calcification of thyroid swellings. Hence, isolated calcification should be surgically treated even if fine needle aspiration cytology is negative for malignancy.     

伴有肋骨侵入椎管的Ⅰ型神经纤维瘤病营养不良型脊柱侧后凸的手术治疗

【摘要】 目的：探讨对伴有肋骨侵入椎管的Ⅰ型神经纤维瘤病营养不良型脊柱侧后凸（neurofibromatosis kyphoscoliosis type 1,NFK-1）患者行单纯后路矫形手术的安全性和早期临床治疗效果。方法：2003年2月~2013年4月共收治8例伴肋骨侵入椎管的Ⅰ型神经纤维瘤病患者,男6例,女2例;年龄7~24岁,平均12.9岁。所有病例肋骨侵入椎管内节段均在侧凸顶点附近1个椎体节段,术前肋骨椎管占位比平均32.86%。其中7例接受单纯后路矫形融合术,1例接受生长棒矫形,均未对突入椎管内肋骨进行直接干预。回顾性分析患者术前、术后及随访时的X线片、CT、脊髓造影后CT（CTM）或MRI,对侧后凸Cobb角、躯干偏移等参数进行测量和分析;同时复习病历,记录围手术期的并发症。结果：手术时间平均为3.3h,术中出血量平均为460ml。固定节段平均为10.1个节段。手术前后胸段冠状面Cobb角分别为67.00°和34.38°,平均矫形率为48.7%。矢状面Cobb角分别为62.50°和31.25°,平均矫形率为49.9%。平均随访时间22.9个月,末次随访时主胸弯冠状面Cobb角及矢状面Cobb角分别为35.75°和33.38°。手术前、后及随访时冠状面躯干平衡分别为35.88mm、15.63mm和14.00mm;矢状位躯干平衡分别为35.13mm、18.13mm和15.50mm。手术前、后椎体旋转度分别为2.25°和1.88°,顶椎偏距分别为49.38mm和35.81mm。7例患者术后复查CT肋骨椎管占位比由术前33.36%减小为术后26.57%;2例肋骨位置未见明显变化,5例肋骨不同程度复位。2例患者术前有胸痛症状,术后胸痛症状均缓解;1例术前右下肢巴氏征（+）、踝阵挛（+）,术后3个月随访病理征转阴性,无神经系统并发症。结论：对于无神经损害症状伴有肋骨侵入椎管内的Ⅰ型神经纤维瘤病脊柱侧后凸患者,对胸段脊柱直接矫形是安全、有效的。     

儿童及青少年颈胸段/上胸段先天性脊柱侧后凸畸形手术治疗的疗效与并发症

目的:评估儿童及青少年颈胸段/上胸段先天性脊柱侧后凸畸形手术治疗的疗效和并发症。方法:回顾性研究2005年4月～2018年1月于我科接受手术治疗的颈胸段及上胸段先天性脊柱侧后凸畸形患者45例,男27例,女18例;年龄10.9±3.1岁(5～15)岁。术前所有患者均存在双肩不等高以及斜颈,2例患者存在脊髓受压及神经功能障碍(均为ASIA D级)。术前均行全脊柱CT平扫及三维重建,畸形顶点位于颈椎12例,位于胸椎33例;形成障碍型24例,分节障碍型5例,混合型16例;28例患者存在代偿性胸弯/胸腰弯;23例患者伴发其他部位的脊柱畸形。所有患者术前均行全脊柱MRI明确椎管内病变情况。对于计划进行颈胸段(C7/T1)截骨或颈椎固定的患者,行双侧椎动脉CT造影(CTA)检查。所有患者均行三柱截骨侧后凸矫形内固定植骨融合术,其中44例患者为单纯后路手术,1例接受C6-7半椎体切除患者行前后路联合手术。截骨水平位于颈椎12例,位于胸椎33例;半椎体切除术32例,全脊椎切除术10例,经椎弓根截骨术3例。6例患者代偿弯行手术治疗,其中4例接受后路融合术,2例接受双生长棒手术。于术后3个月、6个月及1年随访,此后每年进行随访。术前、术后及随访时均摄站立位全脊柱正侧位X线片,对原发侧凸、代偿侧凸及节段性后凸Cobb角与锁骨角、斜颈角度及矢状面平衡(sagittal vertical axis,SVA)进行测量。统计手术时间、术中出血量和手术并发症情况。结果:手术时间为269.1±65.3min(150～310min),术中出血量为987±157ml(500～2700ml)。45例患者均获1年以上随访,随访时间2.8±0.6(1～13)年。原发侧凸Cobb角术前为51.3°±13.9°,术后10.3°±6.4°,末次随访时12.4°±7.5°;代偿侧凸术前为32.1°±23.0°,术后11.1°±21.0°,末次随访时16.3°±23.1°;节段性后凸Cobb角术前为24.2°±15.2°,术后9.2°±8.7°,末次随访时10.4°±9.4°;斜颈术前为19.3°±5.0°,术后4.6°±3.0°,末次随访时5.7°±4.1°;锁骨角术前为7.5°±3.1°,术后2.7°±1.9°,末次随访时2.1°±1.2°;SVA术前为-9.1±16.1mm,术后-12.3±11.2mm,末次随访时-7.5±15.2mm。术后的原发侧凸Cobb角、代偿性侧凸Cobb角、斜颈角度、锁骨角及节段性后凸Cobb角与术前比较均有统计学差异(P0.05),末次随访时的原发侧凸、代偿性侧凸及节段性后凸Cobb角与术后比较有统计学差异(P0.05);SVA术前、术后及末次随访时均在正常范围内,无统计学差异(P0.05)。2例术前存在神经功能障碍者术后完全恢复正常。22例患者发生24例次并发症,其中一过性脊髓损伤伴C8神经根损伤1例,一过性神经根损伤14例,Horner综合征1例,内固定失败2例,血胸3例,切口延迟愈合1例,肺不张1例。结论:三柱截骨术治疗颈胸段及上胸段先天性脊柱侧后凸畸形矫形效果良好,但手术相关并发症风险较高,一过性神经根损伤较为常见,需引起外科医生充分的重视。     

Novel spinal dysplasia in two generations

We report on a father and son with a previously undescribed skeletal abnormality and severe short stature. Antenatal sonographic evaluation of the propositus (son), obtained due to maternal pre-eclampsia, suggested an abnormal spine. At birth, no congenital anomalies were noted and transition to extra-uterine life was smooth. Radiographs performed five days after birth showed spina bifida, hemivertebrae in the mid-thoracic region, and widened lumbar in-terpedicular distances. MRI of the lower thoracic and lumbar vertebrae documented crescent-shaped appearance of the affected vertebrae and abnormally narrow A-P diameter of the vertebral bodies. Intervertebral discs were small, and the posterior elements, as well as the spinous processes of the affected vertebrae, were markedly hypoplas-tic. However, there was no narrowness of the spinal canal, and the limbs were unaffected. CT scan with three-dimensional reformatting of the thoracic and lumbar vertebrae documented unusual sagittal clefting of all of the vertebral bodies, which has previously been undescribed. The father had severe kyphoscoliosis and a height of 131.6 cm (?7.5 S.D.). Radiograph-ically, he was found to have multiple segmentation anomalies and diminished A-P diameter of his affected vertebral bodies. The multiple vertebral anomalies are the probable cause for the father's severe kyphoscoliosis. The pattern of inheritance suggests that an autosomal dominant gene is responsible for this condition and that father represennts a de novo mutationn. These radiographic abnormalities have not been described previously and represent a new form o vertebral spinal dysplasia. © 1995 Wiley-Liss, Inc.     

Dystrophic calcification as a cause for non healing leg ulcers

Despite advances in molecular biology and a repertoire of other therapeutic options, chronic venous leg ulcers remain a significant problem within our society. There are various reasons, both local and systemic, which contribute to the non healing nature of such wounds. Among them, dystrophic calcification (DC) or calcified deposits within the ulcer bed, although rare, is an overlooked and a seldom reported cause. In the presence of DC, wound healing cannot proceed through a timely and orderly manner resulting in a non healing ulcer. In this article, we discuss the aetiology, pathophysiology and the management options of this rarely reported condition. We also report their clinical prognosis using a series of patients with venous ulcers complicated by DC leading to difficulties in healing.